There are several radioactive-labeled pharmaceuticals that preferentially accumulate in focal regions of normal and/or dysfunctional myocardium and associated neurovascular bundles within the atrial and ventricular chambers of the heart. These pharmaceuticals or other similarly labeled compounds can be used to mark the normal or abnormal tissue, depending on the characteristics of those labeled compounds, for subsequent delivery of treatment modalities directly to those marked tissue.
Examples of these radiopharmaceuticals are:                a. C-11, F-18, or Tc-99m labeled annexin-V accumulates in apoptotic cells of the vasculature and myocardium.        b. Radiolabeled Matrix metalloproteinase (MMP) inhibitor, preferentially accumulates in the regions of the myocardium involved in myocardial and vascular injury and fibrosis and repair associated with atrial and ventricular remodeling and have been associated with risk for atrial or ventricular arrhythmias. Radiolabeled In particular, matrix metalloproteinase (MMP) inhibitor, accumulates in myocardial fibrosis. In some embodiments, the MMP inhibitor has an inhibitory constant (Ki) of <1000 nM; in other embodiments, the MMP inhibitor can have an inhibitory constant Ki of <100 nM. Further, in some embodiments, the MMP inhibitor can be an inhibitor of one or more matrix metalloproteinases selected from the group consisting of MMP-2, MMP-9 and MMP-14.        
Fluorodeoxyglucose (18F) (FDG), or fludeoxyglucose F 18 (USAN and USP), also commonly called fluorodeoxyglucose and abbreviated [18F]FDG, 18F-FDG or FDG is a radiopharmaceutical used in the medical imaging modality positron emission tomography (PET). 18F FDG accumulates in inflammatory cells associated with myocardial reperfusion injury following myocardial injury or stress-induced ischemia, or other inflammatory myo-cellular processes within the heart (sarcoidosis, myocarditis), particularly under fasting conditions when myocardial glucose uptake is suppressed. (“The Use of 18F-FDG PET in the Diagnosis of Cardiac Sarcoidosis: A Systematic Review and Metaanalysis Including the Ontario Experience”; George Youssef et al. J Nucl Med (2012); 53:241-248).
Re-186 or Re-188 labeled RDG are also good candidates for infarct imaging.
Thomas Klein et al., using non-invasive external gamma camera imaging, studied three-dimensional 1231-Meta-Iodobenzylguanidine (1-123 labeled mIBG) cardiac innervation maps to assess substrate and successful ablate sites for ventricular tachycardia (VT); (Circ Arrhythmia Electrophysiol. (2015); 8:583-591). He demonstrated that 1231-mIBG innervation defects are larger than bipolar voltage-defined scar and cannot be detected with standard voltage criteria. Thirty-six percent of successful VT ablation sites demonstrated normal voltages (>1.5 mV), but all ablation sites were within the areas of abnormal innervation. 1231-mIBG innervation maps may provide critical information about triggers/substrate modifiers and could improve understanding of VT substrate and facilitate VT ablation.
However, the prior art does not describe or suggest using a detection catheter such as described below to locate the radiation labeled tissue. A beta emitting isotope of iodine, such as 1-124 or 1-131 can be used to label mIBG and the detector catheter as described below can be used to locate the areas of abnormal innervation tagged with the labeled mIBG and then deliver therapy (e.g.; ablation, treatment drugs, cells, etc.) can be delivered directly to the radiation tagged tissue in real time.
Examples of such radiopharmaceuticals that preferentially accumulate in normal myocardium are:                a. Thallium-201, rubidium-82, N-13 NH3, O-15 or O-14 labeled H2O, and Tc-99m labeled sestamibi and tetrofosmin each accumulate in myocardium with normal blood perfusion, and demonstrate no or reduced uptake in ischemic myocardium under stress or in the presence of myocardial infarction.        b. F-18 FDG is also known to accumulate in normal, viable and hibemating myocardium, in the presence of glucose and insulin, and have no or reduced uptake in chronically infarcted tissues under these conditions        c. F-18 LMI1195 or other beta-emitting agents that bind to sympathetic presynaptic and post-synaptic receptors, and accumulate in ganglionic complexes within the heart are predictive of risk for heart failure, arrhythmias, and sudden cardiac death and can be used to guide selective ablation of ganglionic complexes within the heart reducing the risk for arrhythmias. For example, 1-124 or 1-131 labeled MIBG may also be used.The distribution of such radiopharmaceuticals is readily imaged in the heart using gamma cameras or PET scanners.        
Another way of mapping the distribution of radioactivity in an organ is by scanning it with a radiation detection probe. These probes can have single or multiple detectors. These detector probes can be sensitive to gamma rays, beta rays, alpha rays or a combination of these radiations, as well as a selective energy window of these radiations. These probes can also be combined with position sensors (electromagnetic, optical or mechanical), as well as with detectors and cameras of other types of radiations such infra-red, visible light, ultraviolet, or ultrasound.
Method of Delivery of Therapy to Myocardium
The percutaneous delivery of therapies to the myocardium (endocardial surface of atria or ventricles) with directable catheters has become part of routine clinical practice. These catheter-based deliver systems can be guided in the heart based on 2-dimensional or 3-dimensional anatomic locations determined either by external imaging, magnetic field localization using electrode catheters, or electro anatomical mapping of the surface of the heart. These minimally invasive catheter-based systems can deliver a wide range of different types of therapy, including delivery of radiofrequency energy or thermal energy (hot or cold) for ablation of tissues or intramyocardial injection of therapeutic materials. However, the therapeutic delivery of these agents in combination with a diagnostic radio labeled tracer detector probe to locate and pinpoint the specific site for delivery of the therapeutic materials has not been shown or possible in the past. Some more specific examples are outlined below.
Ablation of arrhythmia-generating areas of the myocardium is usually achieved by placing electrodes inside the heart minimally invasively, and pacing the heart until the arrhythmia is induced which is sometimes dangerous. The network of electrodes inside the heart then localize the area that needs ablation which can be performed by local delivery of radiofrequency energy, thermal energy, or cell toxic materials like ethanol.
Ischemic heart disease (IHD) remains a major healthcare issue in the United States, and often results in myocardial infarction (MI) and adverse post-MI LV remodeling, which manifests as changes in LV structure, volume, geometry, and function. An estimated eight million people are afflicted with MI in the United States with around 610,000 new cases reported each year. (Lloyd-Jones D, Adams R J, Brown TM, Camethon M, Dai S, De Simone G, Ferguson T B, Ford E, Furie K and Gillespie C. “Heart disease and stroke statistics-2010 update A report from the American Heart Association”. Circulation, 2010; 121:e46-e215; Go A S, Mozaffarian D, Roger V L, Benjamin E J, Berry J D, Blaha M J, Dai S, Ford E S, Fox C S, Franco S, Fullerton H J, Gillespie C, Hailpem S M, Heit J A, Howard V J, Huffman M D, Judd S E, Kissela B M, Kittner S J, Lackland D T, Lichtman J H, Lisabeth L D, Mackey R H, Magid D J, Marcus G M, Marelli A, Matchar D B, McGuire D K, Mohler E R, 3rd, Moy C S, Mussolino M E, Neumar R W, Nichol G, Pandey D K, Paynter N P, Reeves M J, Sorlie P D, Stein J, Towfighi A, Turan T N, Virani S S, Wong N D, Woo D, Tumer M B, “American Heart Association Statistics C and Stroke Statistics S. Heart disease and stroke statistics—2014 update: a report from the American Heart Association”, Circulation. 2014; 129:e28-e292) The rate and degree of post-MI LV remodeling has been clearly implicated as independent predictors of morbidity, complicating congestive heart failure (CHF), and mortality. The life threatening complications of MI are associated with significant health care costs. The annual medical cost of recurrent MI is approximately $2.4 billion (B), while the annual costs associated with heart failure (1.1 M hospitalizations) exceeds $30.1 B. It is estimated that by 2030 the total cost will increase to nearly $70 B. MI is the leading cause of CHF, which accounts for 35% of all cardiovascular deaths. Post-MI remodeling can be modulated by pharmacological therapy, cellular transplantation, as well as the administration of therapeutic biomaterials. Therefore, these therapeutic approaches that reduce post-MI remodeling will have a major impact on growing health care costs associated with MI and complication CHF.
Over the past decade, cell therapy has emerged as a promising treatment strategy, with a goal of implanting live cells in the infarcted region. Multiple cell types including bone marrow mononuclear cells, bone marrow mesenchymal cells, and adipose tissue-derived cells have been used in acute or convalescent MI, but efficacy has been inconsistent and limited. These cells can be injected into myocardium during surgical procedures, delivered percutaneously via catheters, or delivered antigrade by intracoronary infusion or retrograde through the coronary sinus in patients with ischemic or non-ischemic cardiomyopathy.
Recent clinical trials have demonstrated improved efficacy when cells for treatment are injected directly into the heart tissue either during surgical procedures or percutaneously. This direct delivery results in better retention of cells as reported by Anthony Mathur et. al. in a 2015 review in Circulation Research (Fisher S A, Doree C, Mathur A et al. (2015). “Meta-analysis of cell therapy trials for patients with heart failure”. Circulation Research, 116, (8) 1361-1377.
As an alternative, therapeutic delivery of genes to the heart via direct injection or via intracoronary injection has been demonstrated. (S. R. Eckhouse, B. P. Purcell, J. R. McGarvey, D. Lobb, C. B. Logdon, H. Doviak, J. W. O'Neil, J. A. Schuman, C. P. Novak, K. N. Zellars, S. Pettaway, R. A. Black, A. Khakoo, T. Lee, R. Mukherjee, J. H. Gorman, R. C. Gorman, R. A. Black, J. A. Burdick, F. G. Spinale, “Local Hydrogel Release of Recombinant TIMP-3 Attenuates Adverse Left Ventricular Remodeling after Experimental”, Science Translational Medicine, 6:223ra21, 2014; Brendan P. Purcell D L, Manoj B. Charati, Shauna M. Dorsey, Ryan J. Wade, Kia N. Zellars, Heather Doviak, Sara Pettaway, Christina B. Logdon, James A. Shuman, Parker D. Freels, Joseph H. Gormanlll, Robert C. Gorman, Francis G. Spinale and Jason A. Burdick. “Injectable And Bioresponsive Hydrogels For On-Demand Matrix Metalloproteinase Inhibition” Nature Materials (2014); 13; Burdick J A and Prestwich G D. “Hyaluronic Acid Hydrogels For Biomedical Applications”, Adv Mater. (2011); 23:H41-56; Ifkovits J L, Tous E, Minakawa M, Morita M, Robb J D, Koomalsingh K J, Gorman J H, 3rd, Gorman R C and Burdick J A. “Injectable Hydrogel Properties Influence Infarct Expansion And Extent Of Postinfarction Left Ventricular Remodeling In An Ovine Model”, Proc Natl Acad Sci USA (2010); 107:11507-12; Tous E, Ifkovits J L, Koomalsingh K J, Shuto T, Soeda T, Kondo N, Gorman III J H, Gorman R C and Burdick J A. “Influence Of Injectable Hyaluronic Acid Hydrogel Degradation Behavior On Infarction-Induced Ventricular Remodeling. Biomacromolecules. (2011); 12:4127-4135; Eckhouse S R, Purcell B P, McGarvey J R, Lobb D, Logdon C B, Doviak H, O'Neill J W, Shuman J A, Novack C P, Zellars K N, Pettaway S, Black R A, Khakoo A, Lee T, Mukherjee R, Gorman J H, Gorman R C, Burdick J A and Spinale F G. “Local Hydrogel Release Of Recombinant TIMP-3 Attenuates Adverse Left Ventricular Remodeling After Experimental Myocardial Infarction”. Sci Transl Med. (2014); 6:223ra21; Thorn S, Stacy M R, Purcell B P, Doviak H, Shuman J, Juarez Perez E, Burdick J, FG Spinale and AJ Sinusas. “In Vivo Non-Invasive Evaluation Of Therapeutic Hydrogels For Modulation Of Post Infarction Remodeling: Role Of MMP-Targeted SPECT Myocardial Imaging In A Chronic Porcine Model”, European Heart Journal-Cardiovascular Imaging. (2015); 16; Purcell B P, Lobb D, Charati M B, Dorsey S M, Wade R J, Zellars K N, Doviak H, Pettaway S, Logdon C B, Shuman J A, Freels P D, Gorman J H, 3rd, Gorman R C, Spinale F G and Burdick J A. “Injectable And Bioresponsive Hydrogels For On-Demand Matrix Metalloproteinase Inhibition”, Nat Mater. 2014; 13:653-61.
Many radioisotopes, in addition to gamma rays, emit electrons or positrons (beta rays). Gamma rays travel several centimeters in tissue. Therefore, a detector sensitive to gamma rays will be susceptible to spurious gamma rays emitted by distant organs and background tissue. This background radiation could result in mis-location of small lesions. Beta rays travel just a few millimeters, and therefore a beta ray detector has the advantage of sensing only the local radioactive concentration.
One limitation of gamma probes is their inability to distinguish between the signal and the background radioactivity which obscures small lesions with low tumor/background uptake ratios. The beta probe was invented to circumvent this limitation in traditional gamma probe technology. Since beta rays have short depth of penetration in tissue (˜mm), a beta sensitive probe is not affected by the background radiation.
The Beta detector Probe is ideal for the detection of minute tagged tissue which, due to the short penetration range of beta rays in tissue, is not obscured by the radioactivity accumulated in normal tissues. In an experiment utilizing prostate cancer cells and antibody labeled with I-131, the beta probe was capable of detecting 0.06 g of tumor in presence of 2 mCi of background.
The first intra-operative beta probe was described in U.S. Pat. No. 5,008,546, Daghighian et. al. Intraoperative Beta Probe and Method of Using the Same, and its use is described in F. Daghighian, J. C. Mazziotta, E. J. Hoffman, P. Shenderov, B. Eshaghian, S. Siegel, and M. E. Phelps. “Intraoperative Beta Probe: A Device For Detecting Tissue Labeled With Positron Or Electron Emitting Isotopes During Surgery.”. Medical Physics, 21. No. 1, pp. 153-157, (Jan. 1994) See also R. R. Raylman. “Performance Of A Dual, Solid-State Intraoperative Probe System With 18F, 99mtc, And (111)In.”. Journal of Nuclear Medicine: Society of Nuclear Medicine, 42, No. 2, pp. 352-360, (Feb. 2001) and V. E. Strong, J. Humm, P. Russo, A. Jungbluth, W. D. Wong, F. Daghighian, L. Old, Y. Fong, S. Larson. “A Novel Method To Localize Antibody-Targeted Cancer Deposits Intraoperatively Using Handheld PET Beta And Gamma Probes”. Surgical Endoscoov, 22. p. 386-391, (Nov. 2007), each of which is incorporated herein in their entirety by reference.
The above referenced beta-sensitive probe utilizes a plastic scintillator which is relatively insensitive to gamma radiation (although a small amount is always detected). These spurious gamma rays may become significant when background radioactivity is high. To remedy this, a reference gamma ray detector can be placed near the beta detector for use in subtracting the background gamma rays from the radiation detected by the beta detector.